In the first few weeks of life a newborn chick, poult, duckling or other avian hatchling (xe2x80x9cchickxe2x80x9d) is relatively incompetent at producing antibodies in response to antigenic stimuli. During this period, a significant amount of resistance to infectious diseases is provided by passive immunity derived from maternal antibodies of the hen. However, the presence of passive immunity can also contribute to the immuno-incompetence of the chick during the early post hatching period.
Passive immunity is transferred from the hen to the chick via the egg. IgY antibodies are sequestered from the hen""s serum and secreted in the ovary and incorporated in the yolk before ovulation. The antibodies are stored in the yolk until the later stages of embryonic development when they are absorbed by the embryonic membranes and transferred to the circulation of the chick to provide passive immunity.
Maternally derived antibodies provide immunological protection of the developing chick before active antibody production occurs. However, the presence of maternal antibodies can also interfere with the ability of the young bird to actively respond to an immunogen through a mechanism involving antigen elimination which prevents active immunity to that antigen. Thus, maternal antibodies can act to regulate the immune response by inhibiting development of antibody producing cells.
Typically, food producing animals such as poultry and other livestock (e.g., cattle, swine, sheep, fish, etc.) are immunized as a group at a set period of time. However, within a given population of animals, there are generally variations in the level of maternal antibody and maturation of the immune system between individual animals. For example, chicks from a commercial hatchery may come from many different breeding farms, each having different types and different levels of passive antibodies. In fact, chicks from the same breeder flock may have highly variable antibody titers to the same disease agent. This non-uniformity of passive immune protection can significantly influence the effectiveness of a vaccination program.
In the poultry industry, conventional vaccination programs are designed to be administered after the decline of maternal antibody, typically starting at about 3-4 weeks of age. Under commercial rearing conditions of poultry it is often not feasible to use an injectable vaccine or to immunize birds on an individual basis due to the large number of birds within a flock. Generally, a modified live vaccine is administered by aerosol or water administration at a time at which there is an estimated decline in the level of circulating maternal antibodies against the antigen. However, using live vaccines in the presence of maternal antibodies has a number of inherent disadvantages. For example, to provide sufficient immune stimulation, a live vaccine generally must replicate in the host. The presence of maternal antibodies to that antigen can inhibit replication of a live immunogen resulting in insufficient levels of the immunogen to stimulate an immune response, resulting in a failure to stimulate active immunity. In addition, the consumption of maternal antibodies which were used to inhibit replication of the live immunogen can leave the animal without passive protection. Together or individually, these events can leave the bird unprotected against a field challenge.
Live vaccines also cause significant reactions which can result in decreased body weight, increased mortality, increased medication costs and increased condemnations. The generally held view in the industry""s use of modified live vaccines is that vaccine reaction is a normal and accepted fact of live respiratory vaccine administration and is indicative of the response by the body""s immune system. However, adverse vaccine reactions do not serve a useful purpose and preferably should be prevented.
To overcome the potential problems of vaccinating in the presence of neutralizing maternal antibodies, vaccination programs are used which require administration of multiple immunizations. According to some programs, birds are immunized by aerosol application at, for example, one day, 10-14 days and 21 days of age. The first vaccination is to present the vaccine to those birds that have little or no circulating maternal antibodies. In these birds, the vaccine will induce an immune response and induce a level of protection to prevent early mortality as well as prevent amplifiers of the field virus which could expose the remaining flock to a potential disease outbreak. Subsequent vaccination at days 10-14 and day 21 are to immunize those individuals not responsive to prior immunization due to presence of maternal antibodies.
Another approach to overcome potential problems of vaccinating in the presence of maternal antibodies is to vaccinate an animal with an immunogen repeatedly from day one until they are capable of responding. The stress on the animal and expense for the breeder makes this an unfeasible alternative. In fact, one problem with any repeated immunization program is the requirement for increased handling of the animals which causes stress that can result in a significant reduction in weight gain and efficient feed conversion.
Young animals, including birds can also be immunized en masse after all animals have lost maternal antibodies. A drawback, however, is that there will be a certain percentage of animals who lose passive protection before others and are therefore vulnerable to infection before they are vaccinated.
Yet another approach is to administer, to a young animal, a primary immunizing dose of an immunogen in a preparation that will present the immunogen in a slowly dissipating material. Such preparations include, for example, an injectable water-in-oil emulsion containing a killed antigen, a suspension of an antigen in Freund""s complete adjuvant or phosphatidylcholine (egg-lecithin)- or cholesterol-based liposomes containing an entrapped immunogen. However, such preparations do not provide adequate long-term delivery of an immunogen and may cause adverse reactions such as a granuloma at the site of injection. In addition, there is a risk that the person administering the injection accidentally injects themselves with the preparation, resulting in an adverse reaction from the injected ingredients.
A method for administering a biocompatible implant containing an immunogen at 1-90 days after hatching is disclosed in U.S. Pat. No. 5,538,733, the entire disclosure of this patent is incorporated herein. Methods for in ovo immunization of an avian by injecting a liquid immunogen preparation into a fertile egg during incubation are also known. Such methods of immunization, however, are still subject to the interfering affects of circulating maternal antibodies. That is, interfering maternal antibodies against bacteria, viruses or other agents to which the hen has been exposed are present in the yolk albumin, anmiotic and allantoic fluids and serum throughout embryonic development, prior to hatching. For example, it has been shown that the immunoglobulin IgG is present in the yolk throughout incubation and becomes distributed to the albumen at four days of embryogenesis and in the amniotic as well as in the allantoic fluid at about 12-14 days of incubation. Rose et al., Development and Comparative Immunology, 5:15-20 (1981). IgG is present in the embryo serum from about the 12th day of incubation and in small amounts in the intestine on about the 19th day. Immunoglobulins IgM and IgA have not been shown to be present in the yolk but are present in the albumen and amniotic fluids during about the 12th and 17th day of embryogenesis. Thus, the presence of these maternal antibodies still affect a young bird""s response to a vaccine antigen even if administered in ovo.
Accordingly, there is a need for a method of administering an immunogen to a young bird that can circumvent the interfering affects of maternal antibodies while providing a stimulus for active immunity at the point when the bird is capable of responding to the immunogen. There is also a need to reduce the handling of birds and number of repeat administrations of an immunogen which are presently necessary to assure stimulation of active immunity in substantially all birds of a population.
It will be appreciated that throughout the specification guidance may be provided through lists of examples. In each instance, the recited list serves only as a representative group. It is not meant, however, that the lists are exclusive.
The present disclosure is directed to implants and methods for delivering an agent to an animal. The invention can be particularly advantageous for delivering an agent to a bird in ovo. In one embodiment, the agent can be an immunogen and the method used to induce active immunity in a young bird. This embodiment provides for stimulating active immunity in a population of birds regardless of the immune status of an individual bird. The embodiment advantageously reduces handling, administration repetition and costs associated with most presently available immunization systems.
According to a preferred embodiment of the invention, an immunogen is contained within an implant, or multiple implants, that are administered to a bird in ovo and released into the tissues after administration. In preferred embodiments, the immunogen can be released from the implant at a predetermined time. Thus, a single administration of an immunogen to a population of birds can provide stimulation of active immunity in an individual bird when the individual is sufficiently immunocompetent to mount an immune response against that immunogen.
An implant of the invention can provide for delayed release, sustained release, or a combination thereof, of the immunogen at a selected time after administration. In ovo administration of an immunogen contained in an implant has numerous advantages over conventional vaccination techniques. For example, in ovo administration can reduce the stress associated with handling of the bird. In addition, sustained or delayed release of an immunogen enables each individual bird in a flock to respond to the antigen when the bird becomes immunocompetent. Thus, the internal variability of response to immunization in a flock is reduced and overall vaccine efficacy is increased. The method also reduces vaccine reactions that are often associated with administration of modified live vaccines.